Reviewed & Approved by: Dr. Nihal Ahmad, Professor in Department of Dermatology at the University of Wisconsin, USA

Abstract

Chemotherapy-induced alopecia (CIA), a mucocutaneous side effect of cancer therapy, is often considered by patients to be the most psychologically distressing aspect of treatment. CIA conspicuously announces the illness state, and it decreases quality of life for individuals who are already coping with the physical and psychosocial repercussions of cancer. Currently, CIA is one of the greatest unmet challenges in cancer management, as preventative therapeutic options are lacking. Various treatments have shown differing levels of success in humans and in animal models. The aim of this review is to illustrate the current knowledge on CIA.

Keywords

Alopecia; Chemotherapy; Chemotherapy-induced alopecia

Abbreviations

Introduction

Hair loss, in particular when secondary to chemotherapy, is experienced by patients as a severely negative event [1-8]. No therapy for CIA has demonstrated complete protection against all alopecic chemotherapies in human studies. Both scalp cooling and the immune modulating drug AS101 have reduced the severity of CIA in clinical trials [9-11]. Several therapies have been shown to protect from CIA in animal models. Animal models for CIA have also been crucial in elucidating the mechanisms of CIA. The purpose of this review is to summarize the current knowledge on CIA. The psychosocial consequences, clinical picture, and pathophysiology of CIA will be discussed and tested therapies for CIA surveyed.

A. Psychosocial sequelae of CIA

Alopecia makes patients aware of their own vulnerability [12,13] and serves as a constant reminder of illness and mortality [4]. About half with CIA believe that their cancer diagnosis is obvious to everyone around them despite camouflage with wig use [3]. Patients describe that CIA labels and segregates them in public settings [4,12]. Patients mention not only the loss of scalp hair, but also the loss of eyebrows and eyelashes, as particularly conspicuous. Women express most concern about the loss of hair from the head, eyelashes, and eyebrows while men express concern over hair loss from wider body surfaces [12]. Men and women both experience alopecia as a distressing event [12,14]. Among female patients, 26.7% no longer felt like women after losing their hair [3].

In a pretreatment survey of female breast cancer patients, 8.3% felt so distressed by the likelihood of CIA that they would consider declining chemotherapy [8]. In a 1997 study, 46.6% of patients cited CIA as the single most traumatic side effect of cancer therapy [3]; currently the figure would likely be higher because chemotherapyinduced nausea and vomiting are better managed [15,16]. Several breast cancer patients discussed CIA as more traumatic than the loss of a breast [2]. Some ovarian cancer patients in one study described the experience of chemotherapy-induced alopecia (CIA) as more traumatic than actually having cancer [7].

CIA has been found to alter body image, self-identity, and selfconfidence [1-3,14,17-19]. After CIA, 73.3% of patients felt less selfconfident than they did before [3]. The more severe the degree of alopecia, the lower the psychological wellbeing of the patient [14]. A distress scale for breast cancer patients with CIA was recently developed [19]; patients with higher reported levels of distress from CIA had a greater incidence of depression [20]. Even after regrowth of hair, patients do not necessarily reassume their old identity [21]. Patients with recurrent disease were found to report higher distress associated with hair loss compared to patients with newly diagnosed disease[4].

B. Microscopic and Clinical Characteristics of CIA

Histologic features that characterize chemotherapy-induced abnormalities, or follicular dystrophy, include: disruption of melanin accumulation, irregular banding patterns of the hair shaft, an irregular follicular diameter, a widened hair canal, and distortion of the hair follicle [22]. The cross sectional diameter of regrown hair is smaller after CIA [23]. Furthermore, hairs shed due to CIA have characteristic features when examined trichoscopically, including proximal hair shaft constriction, leading to “Pohl-Pinkus constrictions” and “exclamation mark hair” [24,25].

Whether a patient will develop CIA and to what extent dependchiefly on the drug regimen administered and on the dosage [26]. Drugs found to produce severe alopecia with high incidence include alkylating agents (eg. cyclophosphamide, ifosfamide); anthracyclines (eg. doxorubicin, duanorubicin); antimicrotubule agents (eg. docetaxel and paclitaxel); and topoisomerase inhibitors (eg. etoposide) [26-29]. Combination regimens with two or more agents are associated with greater incidence and severity of alopecia [26].

In CIA, hair loss begins shortly after the initiation of chemotherapy and becomes maximal after 6 weeks [30]. CIA becomes noticeable once approximately 50% of hairs are lost [27-29]. Regrown hair is often initially of a different texture, color, and density [27-29]. Hair growth returns to its normal rate within three months of chemotherapy cessation [30]. CIA was previously thought to be a diffuse alopecia, but instead CIA is characterized by distinct patterns of hair loss that vary by sex [31]. Men lose hair in the Hamilton-Norwood pattern, while women lose hair in the Ludwig pattern [31-35].

There are various grading scales for CIA, including the WHO classification (1981), the Common Terminology Criteria for Adverse Events (CTCAE) (2006, revised in 2010), the Olsen CIA scale (2007), and the Multinational Association of Supportive Care in Cancer (MASCC) (2010) [36]. The WHO and CTCAE 2006 scales use qualitative while the other scales assign percentages of hair loss, and these distinctions are based on approximate clinical assessments [36].

Though CIA is usually reversible, cases of permanent alopecia have been reported [37-39]. Permanent CIA occurs in the rare event that the stem cells in the bulge, which cycle at a slower rate than matrix keratinocytes, are not protected from chemotherapeutic insult [40,41]. Permanent CIA is usually seen after administration of a preconditioning chemotherapeutic regimen before bone marrow transplantation; typical preconditioning regimens include high-dose busulfan with cyclophosphamide or etoposide [37-39]. A recent review found that 12% of pediatric patients who had undergone highdose preconditioning chemotherapy followed by hematopoietic stem cell transplantation developed permanent alopecia [42]. Permanent CIA is not seen exclusively in association with bone marrow transplantation; it has also been reported after treatment for solid organ cancers, for example with standard breast cancer regimens [37,39,43]. Histologically, permanent alopecia is characterized by: an increased ratio of vellus to terminal hairs, an increased ratio of telogen to anagen follicles, and the appearance of basaloid epithelium without evidence of scarring or inflammation [37,39].

C. The Pathophysiology of CIA

There are various mechanisms of CIA, including those that interrupt mitosis, impair metabolic processes, induce cellular damage response pathways, and/or lead to hair matrix cell apoptosis [44]. Various molecular pathways have been implicated in the development of CIA, such as those involving tumor suppressor p53 [45], the p53 mediator and target Fas [13-15, 45-47], and apoptosis regulator Bcl-2 [45,48,49]. Some chemotherapeutic agents, for example doxorubicin, have been shown to damage the hair-follicle vasculature [50] and the sebaceous gland [51]. Others such as cyclophosphamide cause oxidative damage to the follicular pigmentary unit, leading to changes in hair color [22].

HFs most susceptible to CIA are mature, pigmented, late-anagen follicles whose matrix keratinocytes have a rapid rate of proliferation [31,52]. A human scalp HF, which cycles continually, may at any particular moment be in active proliferation (anagen), apoptosisdriven involution (catagen), or relative quiescence (telogen) [52,53]. Of the 100,000 terminal HFs found on the adult human scalp, approximately 90% are in anagen at any given time [54,55]. At the start of each anagen, a population of stem cells from the bulge region, stimulated by factors in the nearby dermal papilla, forms new matrix keratinocytes [56]. During late anagen, these rapidly proliferating keratinocytes terminally differentiate and are compacted into a fiber, the outwardly moving hair shaft [52]. CIA is, then, largely an anagen effluvium [31]. Telogen effluvium, in which resting HFs are shed, has also been reported in CIA, and usually occurs with lower toxicity drugs such as methotrexate and 5-fluorouracil [24].

Based on observations in animal models, there are two main pathways of cellular damage in CIA: “dystrophic anagen” (DysA) and “dystrophic catagen” (DysC) [44,57]. The DysA pathway is induced by lower dose, lower toxicity antineoplastic agents. In the DysA pathway, after insult to the HF there occurs a prolongation of the present anagen, during which time the hair shaft continues to grow but has severely abnormal pigmentation. Subsequently, the HF undergoes an extremely shortened telogen and the hair shaft is shed. Next, a second anagen occurs where the hair shaft is phenotypically normal. The DysC pathway, on the other hand, is induced by higher dose, higher toxicity agents. These more damaging chemotherapeutic insults promptly drive the HF to catagen through a shortened telogen, and the hair shaft is shed. Concurrently, follicular melanogenesis ceases. Hair shedding is followed by a new anagen phase, during which time a normally pigmented hair shaft grows. The DysC pathway is characterized by earlier emergence of phenotypically normal regrown hair in comparison to the DysA [44,57]. Various treatment modalities studied have aimed to take advantage of this phenomenon [44,57,58].

D. Therapy for CIA

Scalp Tourniquet and Scalp Cooling: The first method developed for the prevention of CIA was the scalp tourniquet, which consisted of a blood pressure cuff inflated around the scalp providing mechanical obstruction to scalp perfusion [59-63]. Subsequently, scalp cooling was developed, beginning with Dean et al. who wrapped plastic bags of crushed ice around patients’ heads with a bandage, forming an “ice turban” [64]. The ice turban was placed five minutes before chemotherapy was administered and was left on for the first 30 minutes of treatment; it was well-tolerated, and its effectiveness decreased with increased drug dosage and with each round of chemotherapy [9]. Later, caps were developed utilizing cold air [65], cold gel [66], or glycol-based fluids [67]. Various cooling times and scalp temperatures have been used; the goal is to achieve a scalp temperature of <22°C, which can be done with a preset coolant temperature of 3-8°C [68]. Scalp cooling works by promoting local vasoconstriction, decreasing the uptake of cytotoxic drugs by HFs, and reducing local biochemical activities [9]. Currently, scalp cooling methods are not as widely available in the United States as in Europe because they are not approved by the Food and Drug Administration [26]. There are presently two ongoing clinical trials for scalp cooling therapies in the US [69,70].

Effectiveness of scalp cooling has been reported from 52% to 83% after administration of single-agent chemotherapy [66,71-78]. In one Dutch study, after a single round of chemotherapy, 81% of 53 scalpcooled patients did not require a wig or head covering compared to 27% of 15 controls (p=0.0002) [79]. In another study, during the last round of chemotherapy, 50% of 1,411 scalp-cooled patients did not need to wear a wig or head covering [80]. Effectiveness of scalpcooling is much decreased in patients undergoing chemotherapy with multiple agents. Scalp cooling fails to protect against certain chemotherapeutic classes, such as the taxanes [71,72].

The major concern with scalp cooling is that, with this method, potential scalp metastases might also be protected from the cytotoxic effects of chemotherapy [9,81-83]. This concern is especially pressing in hematologic malignancies where the pre-treatment prevalence of scalp metastases is higher [9]. There are a small number of case reports of scalp metastases discovered after scalp cooling in both hematologic [67,81,82] and solid malignancies [67,72,83,84]; however, it is not clear whether scalp cooling was causative. The incidence of scalp metastasis was found to be low at 9 out of 2500 (0.36%) in a literature review of scalp cooling in CIA from 1973 to 2003 [9].

Side effects of scalp cooling include headache and coldness, which increase with lower coolant temperature [68]. Psychological side effects include increased distress when scalp cooling is unsuccessful [75,85].

Pharmaceutical therapies for CIA studied in humans: Minoxidil, an antihypertensive vasodilator used to promote hair growth in androgenetic alopecia, failed to protect from CIA in clinical trials [86,87], but did protect in an animal model [88] (Table 1). Minoxidil has, however, shown to induce earlier regrowth of hair after CIA in humans [89]. The mechanism of minoxidil appears to be a reduction of the time in telogen, leading to the premature entry of the HF into anagen [90]. Other proposed actions of minoxidil at the HF include prolongation of anagen, increase in HF size, inhibition of collagen synthesis, stimulation of cell proliferation, and increased synthesis of vascular endothelial growth factor (VEGF) and prostaglandins [91].

Table 1: Therapies for CIA tested in animal models.

The immune modulator AS101 significantly reduced CIA in human trials and provided complete protection against CIA in animal models [10,11,92](Table 1). Compared to controls, fewer AS101 patients developed severe alopecia, and more were found to have minimal alopecia [10,11]. The overall difference between AS101 and control groups was statistically significant in two randomized trials of non-small cell lung cancer patients receiving combination carboplatin and etoposide [10,11]. When comparing groups that did not develop any alopecia, however, the difference between AS101 and control groups was not significant in either study [10,11]. Among 44 patients, 26% in the AS101 group had no alopecia after 3 months compared to 10% in the control group [10]. Among 58 patients, 37.2% vs. 20.4% showed no alopecia after three months in AS101 vs. control groups [11].

Vitamin D analogs have not yet demonstrated protection against CIA in humans; they have, however, shown effectiveness in animal models [93-98](Table 1). Topical calcitriol (1,25-hydroxyvitamin D) was tested in a phase I human trial using three different administration doses and schedules; all 12 patients in the treatment arm and the 2 patients in the placebo group developed moderate alopecia by days 20-30 post-chemotherapy [93]. Similarly, no difference was detected between topical calcipotriol or vehicle groups in a study of 24 breast cancer patients receiving a regimen of cyclophosphamide, methotrexate, and 5-fluorouracil [24].

AS101 was found to completely protect from CIA in neonatal rats, and the mechanism was proposed to be via macrophagederived cytokines including interleukin-1 (IL-1) [10,11,92]. Immune cell derived factors, including IL-1, are essential to the mechanism several therapies known to protect against CIA in animals, including IL-1 injected intraperitoneally [99,102], biological response modifier Imuvert delivered intraperitoneally [103,104], and topical immunomodulators cyclosporine A and tacrolimus [105,106] (Table 1).

Topical calcitriol has also shown effectiveness in animal models: it protected against CIA in neonatal rats against etoposide, cyclophosphamide, and combination doxorubicin/cyclophosphamide [95,96]. Topical calcitriol did not effectively prevent cyclophosphamide-induced alopecia in C57BL/6 mice, but enhanced regrowth of normal hair [58] and reduced apoptosis in the hair follicle [97]. In BALB/c mice, topical calcitriol did protect against cyclophosphamide-induced alopecia, but in a sex-dependent way; the effect was more pronounced in male than in female tumor-free mice, and protection increased with increasing tumor burden in tumorladen female mice [98].

In this regard, activating intracellular mechanisms of resistance to toxins is a strategy that could protect against a broad spectrum of chemotherapeutics, as opposed to therapies that protect against only one type of drug like monoclonal antibodies to doxorubicin [129]. Heat shock therapy, which activates a stress protein response, was shown to protect against CIA by four different classes of chemotherapy in three different animal models, and it exhibited no protection of tumor cells [101]. One proposed intracellular target is the ATPbinding cassette (ABC) transporter, which was found to reduce the accumulation of chemotherapeutic drugs, thereby enhancing cellular drug resistance [130].

E. Strategies for coping with CIA

Because there are no therapies yet proven to effectively prevent CIA in humans besides scalp cooling, patients must employ strategies to cope with hair loss. Anticipatory counseling, psychological support, and head coverings are the mainstays of management [26-29]. Some psychosocial tools include anticipating hair loss, coming to terms with the inevitability of it, becoming ready, and taking control [131]. Even if expected, however, alopecia is a traumatic event for patients [6].

Camoflauge techniques, such as wearing a wig, scarf, hat, or other head covering, are central in CIA management [26-29]. Patients can be given a prescription for an “extra-cranial prosthesis” by their oncologist and sometimes their health insurance, if applicable, will cover part or all of the cost of the wig. Patients should plan for a head covering in advance. These methods will protect the scalp from the elements including sun damage, and they often make it easier for the patient to feel incorporated into social life [26-29]. Patients who use a wig to mask CIA report that their wig provides them with support, akin to a “friend” [6]. They affirm that the wig obscures the appearance of illness thereby facilitating evasion of stigma [6].

Gentle hair care techniques are suggested, such as avoiding physical or chemical trauma to the hair, using a satin pillowcase, and combing the hair gently [26]. Also recommended is shaving the scalp or clipping the hair short prior to chemotherapy administration [26-29].

Conclusion

Chemotherapy-induced alopecia is an important condition that greatly impacts the cancer experience; yet, managing CIA and recognizing its psychosocial impact are not always prioritized within cancer care. No single approach has yielded a definitive therapy for CIA in humans, thus far. After CIA occurs, the mainstays of management are psychosocial support and head covering. Animal models for CIA are vital in our understanding of the pathophysiology of the disorder and in development of a future cure. The ideal pharmacologic therapy for CIA protects the HF from a wide spectrum of chemotherapeutic insults and does not interfere with the activity of chemotherapy on tumor cells. Promising therapeutic mechanistic modalities include hair cycle modulation, apoptosis inhibition, and engagement of growth factors and cytokines. Clinical trials complementary to successful animal studies for CIA are required. Also necessary are further clinical studies documenting the incidence, severity, and course of CIA by chemotherapeutic drug.